Abstract Sickle cell disease (SCD) is a hematologic disorder caused by a point mutation in the globin gene. A chronic hypercoagulable state is one of the hallmarks of SCD. Clinical studies demonstrate that SCD patients are at an increased risk of venous thromboembolism, which is associated with increased mortality. Recent studies from our group and others have demonstrated that the hypercoagulable state contributes to chronic vascular inflammation and end-organ damage in mouse models of SCD. These studies strongly suggest that the hypercoagulable state in SCD contributes to disease pathology, rather than being a secondary event. A growing body of evidence indicates that targeting the intrinsic pathway reduces thrombotic risk without affecting hemostasis. Our preliminary results demonstrate that FXII deficiency/inhibition reduces the prothrombotic state in sickle cell mice during both steady state and vaso-occlusive crises. FXIIa-dependent activation of FXI was required only for the increased thrombin generation observed during vaso-occlusive crisis. In contrast, thrombin generation during steady state did not require FXI and instead was mediated by high molecular weight kininogen, Mac-1 integrin and tissue factor. Using mouse models, in vitro experiments and clinical samples, we propose to further investigate the mechanism of FXIIa-dependent thrombin generation in SCD and evaluate the long-term effects of FXII deficiency/inhibition on the prothrombotic state, vascular inflammation and end-organ damage in sickle mice. A better understanding of FXIIa contribution to the pathology of SCD may lead to the development of new, anticoagulant-based therapy that would not increase bleeding risk and could be a part of multimodal approach to prevent cumulative organ damage in patients with SCD.